Uncaging Validity in Preclinical Research

High attrition rates in drug development bedevil drug developers, ethicists, health care professionals, and patients alike. Increasingly, many commentators are suggesting the attrition problem partly relates to prevalent methodological flaws in the conduct and reporting of preclinical studies.

Preclinical efficacy studies involve administering a putative drug to animals (usually mice or rats) that model the disease experienced by humans. The outcome sought in these laboratory experiments is efficacy, making them analogous to Phase 2 or 3 clinical trials.

However, that’s where the similarities end. Unlike trials, preclinical efficacy studies employ a limited repertoire of methodological practices aimed at reducing threats to clinical generalization. These quality-control measures, including randomization, blinding and the performance of a power calculation, are standard in the clinical realm.

This mismatch in scientific rigor hasn’t gone unnoticed, and numerous commentators have urged better design and reporting of preclinical studies. With this in mind, the STREAM research group sought to systematize current initiatives aimed at improving the conduct of preclinical studies. The results of this effort are reported in the July issue of PLoS Medicine.

In brief, we identified 26 guideline documents, extracted their recommendations, and classified each according to the particular validity type – internal, construct, or external – that the recommendation was aimed at addressing. We also identified practices that were most commonly recommended, and used these to create a STREAM checklist for designing and reviewing preclinical studies.

We found that guidelines mainly focused on practices aimed at shoring up internal validity and, to a lesser extent, construct validity. Relatively few guidelines addressed threats to external validity.

The views, opinions and positions expressed by these authors and blogs are theirs and do not necessarily represent that of the Bioethics Research Library and Kennedy Institute of Ethics or Georgetown University.